Bladder cancer is a common disease with an estimated 1 million cases diagnosed worldwide each year. Incidence rates are highest in industrialised countries where over 90% of bladder cancers are of transitional origin. Approximately 75% of patients initially diagnosed with transitional cell carcinoma present with superficial tumours that can be treated by transurethral resection. Clinical management of patients with transitional cell carcinoma is complicated because the recurrence rate of superficial disease is greater than 60% and about 40% of patients with superficial disease will have tumour recurrence within 5 years if treated by trans-urethral resection of tumour alone [Ozono et al., Jpn J Clin Oncol 2001; 31: 536-540]. Furthermore, up to 30% of recurrent bladder tumours will progress to invasive disease [Zieger et al., BJU Int 2000; 85: 824-828]. Thus, early detection and monitoring of patients having, or suspected of having, bladder cancer is important for successful treatment.
The current clinical gold standard for diagnosing bladder cancer involves cystoscopy either under local or general anaesthetic, followed by solid tissue biopsy where that is appropriate. Cystoscopy is routinely used to test patients who present with haematuria or irritative voiding, both symptoms of early transitional cell carcinoma that are more often related to less serious diseases such as urinary tract infection or benign prostatic hyperplasia. Patients with these nonspecific symptoms may undergo extensive urological investigation even though only a small percentage of them actually have malignancies. Because cystoscopy is invasive and costly, both patients and clinicians would greatly benefit from the development of cost-effective and non-invasive tools for the diagnosis and surveillance of bladder cancer. There is, therefore, an urgent need for a reliable, non-invasive screening tool for the diagnosis of bladder cancer.
Cytology analysis of voided urine is the most commonly used non-invasive method for detecting transitional cell carcinoma but its utility is constrained by its low sensitivity other than in cases of high grade malignancy (grade 2 or grade 3).
Previous studies have identified minichromosome maintenance proteins (MCM) as key regulators in the cell cycling process of epithelial tissue [Baldwin et al., Nature Reviews Cancer 2003; 3:217-26, Chatrath et al., British Journal of Cancer 2003 89:1048-54, Sirieix et al., Clinical Cancer Research 2003; 9:2560-6; Davies et al., Lancet 2002; 359: 1917-19; Freeman et al., Clinical Cancer Research 1999; 5: 2121-2132; Stoeber et al., Lancet 1999; 354: 1524-1525; Williams et al., Proc Natl Acad Sci USA 1998; 95: 14932-14937]. Multiple conserved mechanisms limit DNA replication to once per cell cycle. An essential role in proliferation for MCMs and their regulators makes them potentially important biomarkers for routine clinical use in cancer detection and prognosis.
The present invention is based on the finding that there is an association between the number of MCM positive cells in the urine of an individual and their risk of having or developing bladder cancer. Specifically the present inventors have demonstrated that there is a normal range for the number of MCM positive cells one would expect to find in the urine of a healthy individual and patients having a number of positive cells above this normal range are at a significantly increased risk of having, or going on to develop, bladder cancer. In addition the present inventors have extended this finding to patients who have already had cancer and are at an increased risk of relapse.